Candida parapsilosis: A systematic review to inform the World Health Organization fungal priority pathogens list

Abstract Candida parapsilosis is globally distributed and recognised for causing an increasing proportion of invasive Candida infections. It is associated with high crude mortality in all age groups. It has been particularly associated with nosocomial outbreaks, particularly in association with the use of invasive medical devices such as central venous catheters. Candida parapsilosis is one of the pathogens considered in the WHO priority pathogens list, and this review was conducted to inform the ranking of the pathogen in the list. In this systematic review, we searched PubMed and Web of Science to find studies between 2011 and 2021 reporting on the following criteria for C. parapsilosis infections: mortality, morbidity (hospitalisation and disability), drug resistance, preventability, yearly incidence, and distribution/emergence. We identified 336 potentially relevant papers, of which 51 were included in the analyses. The included studies confirmed high mortality rates, ranging from 17.5% to 46.8%. Data on disability and sequelae were sparse. Many reports highlighted concerns with azole resistance, with resistance rates of >10% described in some regions. Annual incidence rates were relatively poorly described, although there was clear evidence that the proportion of candidaemia cases caused by C. parapsilosis increased over time. While this review summarises current data on C.parapsilosis, there remains an urgent need for ongoing research and surveillance to fully understand and manage this increasingly important pathogen.


Introduction
Candida is a genus of yeasts that commonly inhabit the normal microbiome of both humans and animals.Many Candida species have the potential to cause invasive human infections and are associated with significant mortal-ity, approaching 50% globally. 1Whilst C. albicans is historically the most common cause of candidaemia, 2 nonalbicans Candida (NAC) species are becoming increasingly prominent as causative organisms and are of public health concern.
Candida parapsilosis is amongst these clinically significant NAC species, especially in nosocomial settings.Candida parapsilosis is currently the second or third most isolated Candida species in intensive care unit (ICU) populations globally. 3 , 4ther at-risk groups include those receiving total parenteral nutrition and critically ill neonates, 5 partly due to the propensity of C. parapsilosis sensu stricto (and closely related cryptic species C. metapsilosis and C. orthopsilosis ) to form biofilm on indwelling central venous catheters (CVC).However, horizontal transmissions from healthcare workers to inpatients are an added concern in C. parapsilosis infection outbreaks. 5verall, C. parapsilosis is associated with lower mortality than C. albicans , likely related to its lower virulence.Nevertheless, the mortality rate of C. parapsilosis remains unacceptably high. 5Another concern with C. parapsilosis is that resistance to azole and echinocandin antifungal agents appears to be rising. 5espite global concerns about C. parapsilosis , there are limited data on rates of antifungal resistance, population-level morbidity, its impact on healthcare systems, and prevention and control strategies.This systematic review aimed to comprehensively assess several critical aspects of C. parapsilosis infection.We summarised data published between 2011 and 2022 on features including mortality , morbidity , drug resistance, preventability, incidence rates, and geographic distribution patterns to inform the World Health Organizations Fungal Priority Pathogen List (WHO FPPL).We highlight research gaps to inform public health priorities, guide future research, and advocate for improved surveillance.

Methods
After conducting pilot searches to optimise the balance between comprehensiveness and feasibility, we searched the PubMed and Web of Science databases from 1 January 2011 to 18 February 2021.For PubMed, the search was optimised using medical subject headings (MeSH) and/or keyword terms in the title/abstract for each pathogen and criterion.The final search used ( Candida parapsilosis [MeSH terms]) combined, using AND term, with criteria terms including (

mortality [MeSH terms]) OR (morbidity [MeSH Terms]) OR (hospitalisation [MeSH terms]) OR (disability [all fields]) OR (drug resistance, fungal [MeSH terms]) OR (prevention and control [MeSH subheading]) OR (disease transmission, infectious [MeSH terms]) OR (diagnostic [title/abstract]) OR (antifungal agents [MeSH terms]) OR (epidemiology [MeSH terms]) OR (surveillance [title/abstract]).
On Web of Science, MeSH terms are not available, so topic search (TS), title (TI), or abstract (AB) search were used.The final search used (TI = [' Candida parapsilosis '] OR TI = [' C. parapsilosis ']), combined, using AND term, with criteria terms each as topic search, including (mortality) OR (case fatality) OR (morbidity) OR (hospitali * ation) OR (disability) OR (drug resistance) OR (prevention and control) OR (disease transmission) OR (diagnostic) OR (antifungal agents) OR (epidemiology) OR (surveillance).Symbol * allows a truncation search for variations of the term (e.g., hospitalisation or hospitalization).Of note, the search was not limited to invasive human infections caused by C. parapsilosis .
Eligible articles were those reporting data on C. parapsilosis relevant to at least one criterion.Studies could be retrospective or prospective observational studies, randomised controlled trials, or clinical/laboratory surveillance reports.Excluded ar-ticles included those reporting on non-human data (e.g., animals, plants), case reports/conference abstracts/reviews, novel drug studies (preclinical, early phase, or non-randomised controlled trials), in vitro papers on resistance mechanisms, and papers not published in English.
The search results from each database were incorporated into Covidence ® (Veritas Health Innovation, Australia), and duplicates were removed.Two researchers (H.Y.K. and M.A.) independently screened titles and abstracts in parallel based on the inclusion criteria, although no reason was recorded for exclusion during this phase.The remaining articles were subjected to full-text screening for inclusion by the same two researchers.Reasons for exclusion were recorded for all articles during this phase.In both phases, discrepancies were resolved by a third reviewer (J.W.A.).We added any relevant articles identified from full-text screening.
We extracted data from all remaining articles for relevant criteria using standardised report forms within Covidence ® (H.Y.K. and M.A.).The extracted data were checked by the second reviewer (M.A.).
We conducted risk of bias assessments for all included studies using the most suitable tools available: the risk of bias tool for randomised trials version 2 (ROB 2) for randomised controlled trials 6 and the risk of bias in non-randomised studies (RoBANS) tool for non-randomised studies. 7We used each criterion as an outcome of the study and assessed if any bias was expected based on the study design, data collection, or analysis in that study.Studies classified as unclear or high overall risk were still considered for analysis, although the risk of bias was highlighted in analyses.

Results
PubMed and Web of Science Core Collection databases yielded 141 and 236 articles, respectively.After we removed duplicates, 336 articles remained for title/abstract screening.After excluding non-relevant articles, 80 underwent full-text screening, and 51 studies were included in the final analysis.A flow diagram outlining the process of study selection is shown in Figure 1 .
The risk of bias for each study was assessed, and it is presented in Table 1 .Of the included studies, 23 were classified as having a low risk of bias in all domains assessed.A total of 20 studies were classified as unclear risk of bias, mostly due to the selection biases caused by unclear eligibility criteria or population groups or unclear confirmation/consideration of confounding variables.Eight studies were classified as high risk because of selective reporting of results and non-consideration of confounding variables.A summary of the risk assessments is provided to offer transparency and context for the findings.

Deaths
In total, 17 studies reported mortality for invasive infections caused by C. parapsilosis .Using heterogeneous time points encompassing early and late mortality, the crude rates ranged from 14.5% to 47% (Table 2 ).The studies ranged in size from 40 to 660 patients and were mostly retrospective.A total of 13 studies reported 30-day mortality: two studies, from Brazil 8 and Italy, 9 reported high 30-day mortality rates of 45% (18/40) and 46.8% (89/190), respectively, whilst the remaining studies with 30-day mortality reported rates of 17.5%-32.4%.One large study performed a sub-analysis specific for C. parapsilosis from a previous prospective trial in Spain 10 and reported a 30-day all-cause mortality rate of 24.2%.In contrast, a lower 30-day mortality rate was reported (9.8%) in the USA in 2016. 11One study reported a 14-day mortality rate of 5.7% for a pooled cohort of unclear origin, although the study had a high risk of bias due to restrictive inclusion criteria. 12e found that several mortality studies had a high risk of bias due to restrictive inclusion criteria.The study from the USA reporting a mortality rate of 9.8% included only inpatients who survived for at least 4 days after the positive culture was obtained and received initial therapy with only fluconazole or an echinocandin.A study from Turkey included only patients treated with caspofungin and reported a case fatality of 37.8% and a 30-day mortality of 7.5%. 13Another study pooled data from six prospective cohorts but excluded patients from studies if they had received > 48 h of prior antifungal therapy, had prosthetic devices at infection sites that were not able to be removed within 24 h of study entry, or had previously failed treatment for the current episode of Candida infection; this study reported mortality of 14.3% by 28 days. 12Finally, a retrospective study from China included all patients with candidaemia, although C. parapsilosis was the major cause, and reported a mortality rate of 15%. 14

Inpatient care
Four studies reported the length of hospital stays for C. parapsilosis infection, 9 , 11 , 13 , 15 with medians ranging from 18 to 67 days.One study of paediatric patients reported a significantly longer length of stay for isolates with caspofungin minimum inhibitory concentration (MIC) of > 2 μg/ml vs. ≤2 μg/ml (median 67 days, range 14-484 days vs. 65 days, range 26-277). 13he median lengths of stay reported among adults from three separate studies were 18 and 40 days. 9 , 11 , 15However, given the heterogeneity of patients and the small number of studies reporting this metric, no comment can be made on the length of stay directly attributable to C. parapsilosis infection.

Complications and sequelae
No studies reported complications or sequelae specifically related to C. parapsilosis infection.

Antifungal resistance
There were 43 studies on antifungal susceptibility, and most of these studies focused on blood isolates.We have reported the susceptibility of non-sterile site isolates since these may reflect colonising organisms causing invasive infections.An overview of the study type, location, source, and number of isolates is presented in Table 4 .7][18][19][20][21] Whilst five studies reported identifying other members of the C. parapsilosis species-complex ( C. orthopsilosis and C. metapsilosis ), 10 , 18 , 19 , 22 , 23 two studies did not provide specific susceptibilities for C. metapsilosis and C. orthopsilosis due to low isolate numbers. 18 , 22The predominant study type was retrospective cohort ( n = 26), followed by laboratory surveillance studies either retrospectively or prospectively collected ( n = 11).The remaining studies comprised three prospective cohort studies: one in vitro laboratory study, one crosssectional study, and one pooled study sponsored by a pharmaceutical company.The study size ranged from 39 to 1153 isolates, with many studying multiple Candida species and providing some data specific to C. parapsilosis (which accounted for between 10% and 43% of all isolates; see below in the section on distribution). 8 , 14 , 20 , 21 , 24-33Most studies were performed in high-income or upper-middle-income countries (World Bank classification), with no studies in lowincome countries; there was only one study from an African nation during the study window.Data on azole susceptibility and susceptibility to other antifungal agents are presented in Tables 5 and 6 .Most breakpoint interpretations for organism susceptibility utilised guidelines published by the Clinical and Laboratory Standards Institute (CLSI) or the European Committee on Antimicrobial Susceptibility Testing (EUCAST).Given the propensity for C. parapsilosis to form biofilm on foreign material, one study looked at antifungal susceptibility, specifically at different biofilm loads, to ascertain if there was decreased susceptibility. 9One study only provided susceptibility data for C. albicans and NAC, but no specific data for C. parapsilosis . 31usceptibility testing for azole antifungals was reported in 39 studies.Rates of resistance to fluconazole ranged from 0% to 33%.The extensive multi-centre global surveys included isolates collected between 2014 and 2017 and reported fluconazole resistance rates ranging from 3.3% to 8.8%. 34 , 35lthough the reported rates of resistance in these studies increased between earlier and later study periods, the studies are not directly comparable, making a formal analysis of trends impossible.Several single-centre studies reported 0% resistance to fluconazole. 10 , 17 , 20 , 28 , 30 , 32 , 36In two single-centre studies from Italy, higher rates of resistance to fluconazole were reported (22% and 33%, respectively).These higher rates are potentially due to clonal transmission of fluconazoleresistant isolates within the same centre. 3 , 37A single-centre study from Brazil reported 75% resistance to fluconazole; however, this was a composite of isolates: susceptible dosedependent (SDD) and resistant isolates from an outbreak in an ICU, and the study did not provide details on the proportions under each category. 8Fluconazole resistance rates were 1.9% (China), 2.5%-3.4% (Iran), 3.4% (Kuwait), 5% (Spain), 7% (Australia), and 28% (India) in multi-centre studies, 10 , 24 , 27 , 38-41 and 3.8% and 8.8% in two global studies, 34 , 35 respectively.The multi-centre study from India that reported a resistance rate to fluconazole of 28% identified that clonal strains of non-susceptible isolates were circulating in seven of eight Indian hospitals using molecular typing methods. 41A study from Kuwait reported an increase in fluconazole resistance for C. parapsilosis over a 3-year study period between 2012 and 2015. 38ne study assessing the role of biofilm for antifungal susceptibility reported 0% fluconazole resistance for the planktonic form of C. parapsilosis but very high resistance (80%) when testing high biofilm mass and only 10% resistance for moderate biofilm mass.However, only 10 isolates with biofilm mass from each of high, moderate, and low biofilm-forming group were tested. 9usceptibility to posaconazole and voriconazole was reported in 16 and 19 studies, with resistance rates ranging from 0% to 31% and 0% to 18.2%, respectively.Resistance rates of > 10% were reported for posaconazole in one study using broth microdilution EUCAST method 36 and in two for voriconazole. 3 , 37Only one study had susceptibility data for isavuconazole: For 199 isolates, the MIC range was ≤0.03-0.25 μg/ml. 41Only one study reported increasing rates of azole resistance over the study period. 3For the three studies with susceptibility data for C. metapsilosis and C. orthopsilosis , low-level fluconazole resistance is noted for C. metapsilosis .However, the number of isolates relative to C. parapsilosis sensu stricto was reasonably small in each study, and there was no specific pattern. 10 , 19 , 23chinocandin susceptibility was reported in 30 studies (ranging from 9 to 433 isolates) with a mix of testing methods, interpretive criteria, and tested agents, as presented in Table 6 .It should be noted that whilst caspofungin MICs are known to be unreliable, with both EUCAST and CLSI recommending not to perform or report for this agent, 23 of these 30 studies have provided results for caspofungin.There was virtually no echinocandin resistance, with rates reported between 0% and 1.1%, except for one study that only tested for caspofungin susceptibility and reported a 10.2% resistance rate. 17This study, however, utilised Etest strips as the method for which there are no validated interpretive criteria.Another study reported that 86.2% of isolates were susceptible to anidulafungin, but it is not reported how many isolates fell into the intermediate and resistant categories. 12 total of 28 studies reported amphotericin B susceptibility, and 6 reported 0% resistance rates. 21 , 25-27 , 33 , 42Only three studies showed 1.3%-1.6%rates of resistance using CLSI and Etest methods. 17 , 40 , 43A total of 13 studies reported flucytosine susceptibilities with resistance ranging from 0% to 11.6%.The single study reporting > 10% flucytosine 'resistance' utilised epidemiological cutoff values as interpretive breakpoints for flucytosine are not provided by CLSI or  EUCAST. 44Since non-wild-type rates do not equate to clinical resistance, these findings should be interpreted with caution.

Preventability
This section addresses risk factors for C. parapsilosis infection and their mitigation.Three studies (with an unclear or high risk of bias) examined risk factors, but they did not undertake regression analyses to define magnitude. 12 , 13 , 19Risk factors described for C. parapsilosis infection were similar to those established for other forms of candidaemia, such as intensive care admission or intervention and the presence of a CVC.For C. parapsilosis , they included the prior use of echinocandin antifungal agents.Two studies 14 , 33 discussed risk factors for all candidaemia without specifically addressing C. parapsilosis , and 12 reported on risk factors for mortality associated with C. parapsilosis bloodstream infection rather than the risk of infection per se .A multi-variate analysis in one study found that for patients with candidaemia with C. parapsilosis sensu lato , shock and abdominal surgery were independently associated with poorer outcomes, whilst antifungal therapy and central catheter removal were independently associated with better outcomes. 19ix studies assessed preventative measures.Several studies reported nosocomial outbreaks or transmissions of C. parapsilosis candidaemia via biofilm on prosthetic material or CVC but also potentially being carried on the hands of healthcare workers, 3 , 8 , 16 , 20 , 33 , 37 , 41 , 45 , 46 which reflect that effective surveillance and infection-prevention programmes can be preventive measures for C. parapsilosis fungemia, especially CVC-related candidaemia.A study from Spain reported the success of an intervention (in which staff were trained on hospital catheter-related blood-stream infection reduction guidelines) and (undefined) care bundles were implemented.In adult patients, the incidence of catheter-related C. albicans and C. parapsilosis infections fell from 0.53 to 0.36 cases/1000 admissions/year. 47Although not related to infection prevention, three studies reported that early CVC removal ( ≤48 h) reduced the mortality rate. 9 , 10 , 30However, one study showed no difference in mortality with early CVC removal. 48

Annual incidence
Table 9 outlines the nine studies that reported incidence rates of candidaemia due to C. parapsilosis , although the denominator in these is generally institutional rather than the general population.One study, with a low risk of bias, reported a population incidence rate, making a crude estimate of 2.10 per 100 000 population per year. 10

Distribution
Many studies reported the proportion of C. parapsilosis of all Candida bloodstream isolates ranging from 10% to 43%. 8 , 14 , 20 , 21 , 24-33 The proportion was as high as 58% (Brazil) 49 and 70% (Italy), 8 reported in association with outbreaks of C. parapsilosis infection in ICU settings.A study from Iran reported the leading cause of otomycosis cases to be C. parapsilosis (23.9%). 50

Current global distribution
Candida parapsilosis is globally distributed, as evidenced by studies included in this review from Europe, America, Africa, Oceania, and Asia.However, data were limited in many lowand middle-income countries.

Trends in last 10 years
Seven studies reported on the observed trends for C. parapsilosis .Three studies (from China, Italy, and Australia) showed an increase in incidence or prevalence, 20 , 24 , 37 and two (both from Taiwan) showed decreases in incidence. 19 , 48A Malaysian study 51 reported on a change of predominant Candida species for candidaemia from C. albicans in 2001 to C. parapsilosis from 2002 to 2018.No studies provided trend data across the whole study period.Studies that specifically addressed biofilm mass and antifungal susceptibility demonstrated that susceptibility to all antifungal agents within biofilm was much reduced-this may have significant clinical implications given the association of C. parapsilosis with indwelling medical devices.Whilst many studies reported on nosocomial outbreaks or transmission of C. parapsilosis , there was a lack of solid evidence for effective prevention methods.Early removal of central lines reduces the incidence of infection, suggesting that infection-prevention programmes in the hospital that include CVC management in a care bundle may be effective as a preventative strategy.This is an area that requires more studies to generate policy-informing evidence.
The studies in this systematic review show that C. parapsilosis is an emerging fungal pathogen with a wide global distribution.However, data from some WHO regions were missing from this review.The lack of comprehensive data from low-income settings raises concerns.Efforts to enhance international collaboration, data sharing, and surveillance are crucial to better understand regional variations and to inform targeted interventions.Moreover, the scarcity of data on morbidity impacts and complications associated with C. parapsilosis infections warrants further investigation, given the potential for long-term sequelae.Sustainable systematic global surveillance is required to ensure that critical regional variations in incidence and epidemiology can be monitored for this as well as other fungal pathogens.

Conclusion
This systematic review has identified several critical knowledge gaps.There is a significant lack of data from low-income settings, especially related to incidence, prevalence among candidaemia cases, mortality, and non-fatal burden.Most reports on susceptibility came from laboratory surveillance without clinical correlation.This makes it difficult to assess the impact of observed changes in susceptibility and is a barrier to developing clinical breakpoints.
There was a general lack of clinical data, especially around morbidity impacts.We have summarised current data on C. parapsilosis and highlighted where ongoing research and surveillance are required to better understand this increasingly important pathogen.Specifically, research should focus on large clinical cohorts, which can be used to better understand the burden of disease and form the basis of future prevention and therapeutic studies.Health economic impacts must be included.It will also be important to enrol both adult and paediatric patients across different patient cohorts and harmonise outcome measures to allow comparisons across time and geographies.
In conclusion, this systematic review provides valuable insights into the clinical and public health implications of C. parapsilosis infections.The identified knowledge gaps underscore the need for concerted efforts in research, surveillance, and prevention.Addressing the gaps in our understanding of this pathogen's impact on patient outcomes and healthcare systems is essential to guide intervention strategies and improve patient care and outcomes.

Figure 1 .
Figure 1.Flow diagram for selection of studies included in the systematic review.

Table 1 .
Risk of bias.

Table 3 .
Length of stay.

Table 4 .
Studies reporting drug susceptibility.
A uthor,

Table 5 .
Continued Data and interpretive breakpoints are presented here as reported in source documents.
A uthor,

Table 8 .
P re v entativ e measures.

Table 10 .
Proportion of C. parapsilosis causing candida infection.

Table 11 .
Trends in the last 10 years.
Note: ND, not determined.